There is a great need to find effective drugs for variety of high prevalence cancers, e.g., breast cancer, prostrate cancer and complicated cancers such as the pancreatic cancers. In the United States, the prevalence of these cancer types is: breast—2,369,036; prostate—1,937,798 and pancreas—27,688. The incidences reported in 2006 in the United States for these cancers are: breast—180,510; prostate—218,890; pancreas—37,170.
Among the aforementioned cancer types, patients with pancreatic cancer have a high mortality rate. Treatment of pancreatic cancer is rarely successful because this disease has usually metastasized widely by the time it is diagnosed. Therapy consists of surgery and, possibly, radiation and chemotherapy. Presently, there is no approved drug designed exclusively for pancreatic cancer and drugs used in other cancer conditions are now prescribed for pancreatic cancer patients; e.g., gemcitabine is currently used to treat pancreatic cancer. There are several clinical trials underway for pancreatic cancer using various drug combinations.
One of the main causative factors of cancer is defects in the apoptotic pathways (Korsmeyer, Blood 80: 879-886, 1992; Hager et al., Ann. N.Y. Acad. Sci., 887: 150-163, 1999). These defects arise out of a loss of regulatory controls as a result of altered gene dosages via gene mutation, deletion or duplication either in autocrine growth signals involved in cell-to-cell communication (e.g., EGF, TNF, NF1, Wnt), or in cell-cycle control factors (e.g., p53 or ABL), or an increase in oncogenes such as Ras, PKB or ABL (Harris, IUBMB Life 55: 117-126, 2003).
In most of the aforementioned cancers it has been shown that there is an overexpression of epidermal growth factor receptor (EGFR) leading to activation of the Akt and NF-κB signalling pathways, suggesting that these pathways are important targets. It has been shown that Akt can inhibit death by apoptosis induced by various stimuli in a certain number of cell types and in tumor cells. In accordance with these findings, it has been shown that Akt can, via phosphorylation of given serine residues, inactivate BAD, GSK3.beta., caspase-9 and Forkhead transcription factor, and activate IKKalpha and e-NOS. Various experimental data suggest that the activation of EGFR leads to the activation of Akt which in turn activates NF-κB and, hence, strategies to disrupt this pathway or down regulate EGFR/NF-κB may be useful for achieving maximal therapeutic response in these cancers.
Epidemiological surveys have provided evidence that consumption of certain phytochemicals through diets/specific foods is associated with reduced risk of several types of cancers (Ghaneh et al., J. Hepatobilitary Pancreat Surg., 9: 1-11, 2002; Lee et al., Cancer Epidemol. Biomarkers Pren., 12: 665-668, 2003; Mukhtar et al., Toxicol. Sci., 52: 111-117, 1999). These phytochemicals generally act as competitive inhibitors of ATP and/or non-competitive inhibitors with substrate molecules. However, they are of little use in themselves since they are broad range inhibitors and are effective only when used at high concentrations. On the other hand they can prove to be valuable as models in designing synthetic molecules that can disrupt the phosphorylation reactions as well as signal transduction processes. Thus, synthetic manipulations of certain phytochemicals may be beneficial for evolving highly efficient and selective therapeutic agents, particularly those targeting specific proteins in signal transduction processes.
The majority of oncogenic cell-cycle control factors belong to one of the several families of protein kinases, which are involved in a number of key cell survival, growth and proliferation signal transduction pathways. These can be roughly divided into two major types: protein tyrosine kinases and serine/threonine protein kinases. Among these, Akt signaling is an important signal transduction pathway in cells. Akt is also referred to as protein knase B (PKB), which plays a critical role in controlling the balance between cell survival and apoptosis (Levitz et al., Science, 267: 1782-1788, 1995). Akt contains an amino terminal pleckstrin homology (PH) domain that binds phosphorylated lipids at the membrane in response to activation of PI3 kinases. Akt may be activated by insulin and various growth and survival factors through activation of PI3 kinase (Franke et al., Cell, 88: 435-437, 1997; Burgeving et al., Nature, 376: 599-602, 1995). Binding of growth factors to their receptors activates PI-3K, comprised of 85 kDa and 110 kDa subunits. PI-3K converts phosphatidylinositol-4,5-bisphosphate (PIP2) to PIP3, while the lipid phosphatase PTEN reverts this reaction. PKB binds to PIP3 via its PH domain, where it is phosphorylated on two key residues by upstream kinases. Akt is activated by phospholipid binding and phosphorylation at Thr308 by PDK1 (Franke et al., Cell, 727-736, 1995), and also by phosphorylation within the C-terminus at Ser473 by PDK2. PDK1 is localized to the plasma membrane via high-affinity binding of its PH domain to basal levels of PIP3. Following phosphorylation at the plasma membrane, activated PKB translocates to the cytosol, where it is dephosphorylated and inactivated by PP2A. Akt promotes cell survival by inhibiting apoptosis by its ability to phosphorylate and inactivate several targets including Bad, Forkhead transcription factors and caspase-9, all of which are involved in the apoptotic pathway (Alessi et al., EMBO J., 15: 6541-6551, 1996; Brunet et al., Cell, 96, 857-868, 1999; Rommel et al., Science, 286: 1738-1741, 1999). Recent reports showed that Akt also regulates the NF-κB pathway via phosphorylation and activation of molecules in the NF-κB pathway (Romashkova et al., Nature, 401, 86-90, 1999; Nozes et al., Nature, 401: 82-85, 1999).
Akt plays an important role in cancer pathologies. The amplification and/or overexpression of Akt has been reported in many human tumors, for instance gastric carcinoma (amplification of AKT1), ovarian, breast or pancreatic carcinomas (amplification and overexpression of AKT2) and breast carcinomas deficient in estrogen receptors, and also androgen-independent prostate carcinomas (overexpression of AKT3). Furthermore, Akt is constitutively activated in all PTEN (−/−) tumors, the phosphatase PTEN being deleted or inactivated via mutations in many types of tumors, for instance ovarian, prostate and endometrial carcinomas, glioblastomas and melanomas. Akt is also involved in the oncogenic activation of bcr-abl (Sarkar et al., Toxicol. Appl. Pharmacol., In Press, 2006; Khawaja, Nature, 401: 33-34, 1999; Cardone et al., Nature, 282: 1318-1321, 1998; Kitada et al., Am. J. Pathol., 152: 51-61, 1998; Mazure et al., Blood, 90: 3322-3331, 1997; Zhong et al., Cancer Res., 60: 1541-1545, 2000).